This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), human T-lymphotropic virus types I and II (HTLV-I/-II), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). The Second Multicenter Hemophilia Cohort Study (MHCS-II) has enrolled and begun prospective follow-up of more than 2000 HCV-exposed persons with hemophilia. Testing of the cohort has been initiated with newly developed Taq-Man PCR assays for detection and quantification of HCV and HIV RNA have been developed and with a newly developed sequence-based method to determine HCV genotype. Initial analyses suggest that spontaneous clearance of HCV is associated with infection relatively recent calendary years. Analyses of data from the preceding first MHCS show that non-Hodgkin lymphoma risk is very strongly related to HIV infection and older age but not to HCV or hepatitis B virus (HBV) infection. In contrast, hepatocellular carcinoma risk is strongly related to HCV infection and older age, HIV infection, or HBV infection. Use of alcohol, acetaminophen, and non-steroidal anti-inflammatory drugs, all of which may be hepatotoxic, is generally low. In a collaboration, AIDS progression rate was related to differences in genes (HLA class I and KIR) affecting innate immunity. With KSHV infection without HIV co-infection, risk for classical (non-AIDS) Kaposi sarcoma was increased with detection of KSHV in peripheral blood and with certain variants in host genes related to anti-inflammatory cytokines and immunoglobulin binding. Laboratory and field studies to clarify these associations are in progress.Among carriers of HTLV-I infection, those in Japan were found to have lower levels of HTLV-I antibodies but higher HTLV-I proviral load in peripheral blood cells than those in Jamaica. This pattern mirrors the contrasting risk of the two major outcomes of HTLV-I infection (adult T-cell leukemia/lymphoma and tropical spastic paraparesis) in these two populations.In a large cohort of injection drug users, HCV viral load was significantly higher with HIV-1 and/or HTLV-II co-infection, as well as for white men and those with longer HCV infection. In the same cohort, mortality due to liver disease was directly related to HCV viral load, which appeared to account for previously reported associations of hepatic mortality with male gender and HIV-1 co-infection.